PROJECT SUMMARY/ ABSTRACT Given the substantial morbidity and mortality associated with a diagnosis of breast cancer, the identification of modifiable risk factors and women at high risk for breast cancer is imperative. Body mass index (BMI), a general measure of overall adiposity, is a risk factor that has been well established to be inversely related to premenopausal breast cancer and positively associated with postmenopausal breast cancer. In contrast, central adiposity, measured by waist circumference (WC) or waist-to-hip ratio (WHR), is characterized by high levels of metabolically active visceral fat that leads to alterations in multiple hormones (e.g., insulin), inflammatory cytokines, and adipokines, all of which have been implicated in breast cancer development. Thus, I hypothesize that measures of central adiposity provide further information about breast cancer risk and survival in addition to BMI. To date, few studies have had the statistical power to evaluate the link with premenopausal breast cancers and even fewer have evaluated associations according to important tumor characteristics and molecular subtypes. Therefore, I propose to improve understanding of the role of central adiposity in breast cancer risk and survival. I aim to: 1) examine the independent association of central adiposity with breast cancer risk by menopausal status and determine whether significant predictive information is gained by adding central adiposity to the validated Rosner-Colditz risk prediction model; 2) examine the relationship by tumor molecular subtypes; 3) examine the relationship by several key tumor characteristics (i.e., estrogen receptor, androgen receptor, insulin receptor expression, PTEN loss, PIK3CA mutations); and 4) lastly examine the association between central obesity and breast cancer survival. To address these aims, I will utilize the rich questionnaire and biospecimen resources from two large prospective cohorts, the Nurses' Health Study and Nurses' Health Study II. The women reported waist and hip circumferences at two time points and breast cancer that was confirmed via medical record review. Additionally, I have information on several tumor characteristics measured from available breast tumor tissue blocks. With a large number of premenopausal breast cancer cases, multiple waist measurements, long follow- up, and detailed tumor data, I will improve understanding of central obesity's role in breast carcinogenesis. By evaluating subtypes and tumor characteristics, I should gain substantial new insight into biological mechanisms and help confirm causality. This will allow us to identify women at higher risk for breast cancer development and lower risk of breast cancer survival. Secondly, results gained from this work may improve risk prediction models to help identify women at high risk of developing breast cancer who would be potential candidates for potential chemoprevention or other risk-reducing options (e.g., increasing physical activity).